1. Field of the Invention
The present invention relates to the use of 5-trifluoromethyl-1-(5-chloro-2-hydroxyphenyl)l,3-dihydro-2H-benzimidazol- 2-one (NSOO4) for therapy of cystic fibrosis and multi-drug resistance in cancer chemotherapy.
2. Background Art
Cystic fibrosis (CF) is a lethal genetic disease afflicting nearly 30,000 people in the United States. In individuals of Northern European extraction, approximately 1 in 2500 newborns is born with the disease, making it the most common lethal, recessively inherited disease among Caucasians (although the disease is present in non-white populations as well). First described in the 1930's, CF was initially thought to be a gastrointestinal disease, as individuals died from malnutrition and inanition (lack of vitality), often in the first year. In particular, the name cystic fibrosis was derived from the original description of the disease as `cystic fibrosis of the pancreas`, which reflected the destruction of pancreatic exocrine function in these patients.
Excessive salt loss occurs in the sweat of children with CF, and the level of sodium and chloride (Cl.sup.-) in the sweat was first used as a diagnostic in the 1950's. A decade ago the abnormal levels of salt transport in the sweat of CF patients was attributed to dysfunctional Cl.sup.- transport in sweat ducts, and reduced Cl.sup.- transport in respiratory epithelia was discovered almost simultaneously.
Currently, cystic fibrosis is primarily thought of as a respiratory disease, characterized by airway obstruction due to thick, sticky mucous and serious secondary complications resulting from bacterial infections. Intestinal and pancreatic obstructions and insufficiency are also present in many cases.
Although cystic fibrosis is a single-gene disorder, identification of the gene and gene product(s) responsible for CF proved difficult prior to the discovery that the normal apical epithelial cell Cl.sup.- efflux in respiratory tissues that occurred in response to cAMP stimulation (via .beta.-adrenergic receptor activation) was blunted or absent in CF tissues. This was subsequently shown to reflect a lack of cAMP-dependent protein kinase A-dependent activation of a Cl.sup.- conductance in the epithelial cells. (Cotton, C. U., et al., J. Clin. Invest., 79: 80-85 (1987); Welsh, M. J., FASEB J., 4: 2718-2725 (1990)). These discoveries led to the characterization of the cystic fibrosis transmembrane conductance regulator (CFTR), the gene product responsible for cAMP-activated Cl.sup.- conductance. (Rommens, J. M., et al., Science, 245: 1059-1065, (1989); Riordan, J. R., et al., Science, 245: 1066-1072 (1989); Bear, C., et al., J. Biol. Chem., 266: 19142-19145 (1991)). The cystic fibrosis transmembrane conductance regulator is a 1480 amino acid protein that is a member of a large family of ATP-binding cassette transporters (ABC transporters) which includes the multi-drug resistance gene (MDR) and its gene product, P-glycoprotein. (Higgins, C. F. Ann. Rev. Cell Biol., 8: 67-113 (1992); Hyde, S. C., et al., Nature, 346: 362-365: 1990)). It has now been established that CFTR is a linear Cl.sup.- channel when (a) ATP is bound to two nucleotide binding domains in the protein and (b) cAMP-dependent phosphorylation of a regulatory domain occurs. Recent evidence also suggests that CFTR may control other proteins, including the conductance of an outwardly rectifying Cl.sup.- channel. (Gabriel, S. E., et al., Nature, 363: 263-266 (1993)). Many mutations of CFTR have now been reported, many clustered in the first nucleotide binding domain. Included in this group of mutations is the .DELTA.F508 CFTR mutant that is responsible for approximately 70% of CF in the United States. (Collins, F. S., Science, 256: 774-779 (1992); Kerem, B. S., et al., Science, 245: 1073-1080 (1989)). While it is likely the case that the protein undergoes some degree of temperature-sensitive biosynthetic arrest in cells expressing the .DELTA.F508 CFTR mutant, those channels that are expressed appear to have a deficient response to cAMP stimulation resulting in greatly reduced cAMP-dependent Cl.sup.- current. (Dalemans, W., et al., Nature, 354: 526-528 (1991); Drumm, M. L., et al., Science, 254: 1797-99 (1991)). Proposed therapies for treating CF therefore include gene therapy to transfect airway epithelial cells with normal CFTR to restore Cl.sup.- function, the development of `escort` molecules to enhance normal processing of the .DELTA.F508 gene product, and drug therapy to increase Cl.sup.- conductance through mutant CFTR channels or other Cl.sup.- channels that may be under the control of CFTR.
The agent NSOO4, chemically 5-trifluoromethyl-1-(5-chloro-2-hydroxyphenyl)-1,3-dihydro-2H-benzimidazol -2-one, was disclosed by Olsen, et al, in U.S. Pat. No. 5,200,422 as a member of a series of benzimidazole compounds claimed to be useful in treating diseases which are benefited by the opening of cell membrane potassium channels.
A treatment for cystic fibrosis involving the administration of aerosolized sparteine was disclosed and claimed by Agus, et al, in U.S. Pat. No. 5,100,647. Sparteine chemically is dodecahydro-7,14-methano-2H,6H-di-pyrido[1,2-a;1',2'-e][1,5]diazocine. Agus, et al, describe sparteine as activating chloride channels at low doses but as blocking chloride channels at higher doses. There is nothing in the art to suggest the use of NSOO4, a potassium channel opener, for treating chloride conductance-related disorders such as cystic fibrosis.